PROJECT SUMMARY/ABSTRACT Respiratory syncytial virus (RSV) is a common respiratory virus that usually causes mild, cold-like symptoms. Most people recover within two weeks, but RSV is the most common cause of bronchiolitis and pneumonia in children under one year of age, and leads to hospitalization of ~177,000 adults aged 65 and older of which ~14,000 die annually. Despite many attempts, a vaccine to protect these at-risk populations from RSV infection remains elusive. To remediate this critical unmet need, Codagenix has applied its core technology, Synthetic Attenuated Virus Engineering (SAVE) to the development of an RSV vaccine. SAVE is based on rational, computer-aided gene design and chemical synthesis to produce live attenuated viruses through gene ?deoptimization.? SAVE generates live-attenuated viruses that are 100% antigenically identical to wild type virus in all their proteins. MinL4.0, our lead RSV vaccine candidate contains 1,378 synonymous mutations in the polymerase L open reading frame. It grows well at 32C, is highly attenuated, displays wt-like immunogenicity, and is genetically stable for at least 8 passages at 32C in Vero cells. In this Phase IIb SBIR, we will build on our successful Phase II SBIR and subsequent studies to further develop MinL4.0. Our initial target patient population will be adults aged 50-75, a population that is at-risk for severe RSV disease. In this Phase IIb work, we will reformulate MinL4.0 to make it commercially suitable for intranasal administration and storage and then perform FDA-required stability and release testing of the re-formulated vaccine. We will also perform preclinical safety and efficacy testing in cotton rats. No animal model of RSV recapitulates all of the aspects of human RSV disease, but the cotton rat is probably the best small animal model. The cotton rat is relatively permissive, can be infected throughout its life, exhibits immuno-senescence, including T-cell loss as is found in older humans, and, like humans, is less resistant to RSV infection with age. Even though most adults have some immunity to RSV and elderly adults are at risk for severe RSV infections, vaccine studies are typically performed in young RSV nave animals. Here, we will develop a new model of RSV pre-immunity in aged cotton rats to more accurately model conditions found in older adults and serve as a more relevant and stringent pre-clinical test of safety and efficacy that can be used by others. We will then test the safety and efficacy of MinL4.0 in this new pre-immune aged cotton rat model of RSV disease. Our animal studies will be conducted in partnership with Sigmovir, a contract research organization whose sole focus is the study of infectious human diseases in the cotton rat model. Finally, based on these and other data, we will complete all required documentation and submit an Investigational New Device (IND) application to the US Food and Drug Administration (FDA) in order to conduct Phase I clinical trials in adults 50-75 years of age.